The pregnant uterine mucosa, called decidua, contains ~15-30% of leukocytes in early pregnancy in humans. Recent studies have detected natural killer T cells in human and mouse decidua. The murine peri-implantation uterus contains an expanded population of natural killer T cells, but their function in pregnancy remains unclear. Natural killer T cells are known to react with lipid antigens bound to a non-classical MHC class I-like lipid antigen presenting molecule called CD1d. In preliminary work, we have identified T cells that react with phospholipid (PL) antigens in the decidua, and lymphoid organs of mice as well as in peripheral blood of humans. These novel PL-reactive T cells (PL-T) are relatively abundant in the decidua compared to lymphoid organs in mice and secrete cytokines upon immunization with PL antigens in vivo. The PL-T cells are restricted by CD1d. Such PL-T cells are relatively more in the decidua of lupus mice than in healthy strains. The goal of this R21 Exploratory proposal is to understand the role of PL-T cells in immune-mediated pregnancy loss. Guided by our novel observations, we hypothesize that PL-T cells are altered in lupus mice; such altered PL-T cells induce pregnancy loss. In Aim 1, we will determine the role of PL-T cells on pregnancy outcome in mice with lupus and anti-phospholipid syndrome. In Aim 2, we will begin to translate animal findings. Specifically, we will determine if PL-T cells exist in the decidua of humans, and whether peripheral blood and decidual PL-T cells from patients with lupus/anti-phospholipid syndrome display an activated phenotype with increased production of pro-inflammatory cytokines compared to PL-T cells from normal pregnant women. It is hoped that the study will advance our understanding of decidual immune cells in fetal health and elucidate a novel pathogenetic mechanism of immune-mediated pregnancy loss in lupus and autoimmune diseases.